An ultrasound-controllable ROS-responsive nanoplatform for O₂ and NO generation to enhance sonodynamic therapy...

Antimicrobial sonodynamic therapy (SDT) has broad application potential in the eradication of multidrug-resistant (MDR) bacterial infections due to its non-invasiveness, absence of resistance concern, and high cytotoxicity. However, the hypoxic infection microenvironment and the rapid depletion of O₂ during SDT severely limit the therapeutic efficacy of SDT. Herein, an ultrasound-controllable ROS-responsive nanoplatform (FOT/Fe₃O₄@Lipo-ICG) was constructed and prepared by encapsulating FOT and Fe₃O₄ nanoparticles (Fe₃O₄ NPs) within sonosensitiser ICG-modified liposomes. Both in vitro and in vivo, we observed that ICG conjugation on the surface of liposomes could effectively maintain good dispersion and prevent ICG aggregates in complex biological matrices. In addition, liposomes could significantly block the catalytic activity of Fe₃O₄ NPs, as well as the release of FOT, whereas upon US irradiation, the catalytic activity of Fe₃O₄ NPs was recovered to catalyse the decomposition of endogenous H₂O₂ into O₂ and ˙OH. Meanwhile, the FOT was successfully released to react with endogenous glutathione to sequentially produce NO. Based on the aforementioned advantages, the FOT/Fe₃O₄@Lipo-ICG demonstrated potent efficacy in eradicating methicillin-resistant Staphylococcus aureus-induced local infection and sepsis resulting from local infection. Thus, the developed US-controllable nanoplatform offers a promising strategy for enhancing SDT for eradicating MDR bacterial infections.